The overall goal of my research is to understand quorum sensing: the process of cell-cell communication in bacteria. Until recently, the ability of bacteria to communicate was considered an anomaly that occurred only in a few marine vibrio species. It is now clear that cell-cell communication is the norm in the bacterial world and that understanding this process is fundamental to all of microbiology, including industrial and clinical microbiology, and ultimately to understanding collective behaviors and development in higher organisms. We showed that Vibrio cholerae, a major pathogen in under-developed countries, has a quorum-sensing system and that this system controls virulence. We discovered that multiple quorum-sensing signals are channeled into one signaling circuit;yet the circuit enables differential gene expression in response to the different signal inputs. We also recently discovered that four redundant small regulatory RNAs (sRNAs) lie at the heart of the V. cholerae circuit, and that they mediate the quorum-sensing switch allowing V. cholerae cells to transition from acting as individuals to functioning as a coordinated group. Thus, the V. cholerae quorum- sensing circuit has revealed itself to be ideally suited for explorations of questions concerning how sensory information is integrated at the molecular level and how regulatory proteins controlled by multiple cues can nonetheless provide a mechanism for differential responses to those inputs. We will study V. cholerae to learn the mechanism by which sRNAs regulate behavior, and to discover the unique control features provided by sRNA regulators (as opposed to DNA-binding proteins). Finally, we will use V. cholerae to examine the molecular switch underlying quorum sensing, how individual behaviors give rise to collective behaviors, and to identify the genes that are critical for survival as an individual and as a member of a coordinated community. The above questions are the focus of this research application. At the most general level, these studies will provide insight into intra- and inter-species communication, population-level cooperation, and the network principles underlying signal transduction and information processing at the cellular level. At a more specific level, these studies will advance our understanding of the mechanisms of sRNA-mediated control of gene expression, the global nature of which has been, until recently, under- appreciated and under-studied in bacteria. Finally, at a practical level, these investigations could lead to synthetic strategies for controlling quorum sensing. Objectives include development of anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence, and improved industrial production of natural products such as antibiotics.